The long-term objective of this project is to develop short- and long-acting antibody-based medications for the treatment of drug abuse. Medications are badly needed since repeated use of these drugs can lead to toxicity, psychosis, violent behavior and addiction. These new medications could be used in an emergency room setting for rapidly reversing a drug overdose or in a treatment plan for a recovering addict. Although the long-term goal is to learn how to best use antibody-based "pharmacokinetic antagonists" for treating a wide range of drugs, the main focus of this project will be on phencyclidine (PCP). The experiments in this proposal are designed to systematically test the hypothesis that anti-PCP IgG monoclonal antibodies (MAb) and their antigen binding fragments (Fab) could be used to treat the medical problems associated with PCP abuse. The first studies will address the biopharmaceutical and clinical strategies for anti-PCP Fab treatment of PCP overdose in dogs. In the second studies, mouse MAb with a wide range of affinity constants (from about 1-300 nM) will be generated for use as potential long-acting antagonists of repeated PCP use. These antibody medications will then be used in rats to test our hypothesis that careful selection of antibody affinity can lead to an optimal balance between drug association with the antibody (to block drug effects), and drug dissociation from the antibody (to allow regeneration of antibody binding capacity). Combined pharmacokinetic and pharmacodynamic analysis of these experiments will allow us to design better clinical strategies for using antibody-based medications. In the final series of experiments, we will study the rates of partitioning into, and out of, the rodent brain without and with treatment with our antibody-based medications. These data will help to determine the ability of the MAb to redistribute the drug and the rate at which drugs of abuse enter and leave the brain. These integrated studies of pharmacokinetic, behavioral and central nervous system changes before and after antibody-based therapy will serve as a prototypic model that can be applied to treatment of drugs of abuse in humans.